SBIR-STTR Award

Every year, 150,000 Americans are affected by Acute Respiratory Distress Syndrome (ARDS), an inflammatory lung condition that may complicate severe pneumonia (including influenza and COVID-19), trauma, sepsis, cancer, and many other conditions. The mortality of ARDS is 27%, 32%, and 45% for mild, moderate, and severe disease, respectively. The survival rate for COVID-19 patients with ARDS is about 25%. There is no proven drug treatment for ARDS per se. This highlights an urgent need for effective treatment of ARDS. The long-term goal of this project is to develop an effective and well-tolerable ARDS therapy aimed to reduce the mortality rate and improve outcomes in ARDS patients. Amplified, rapid acute inflammatory response in the lungs in ARDS is associated with cytokine storm. Triggering receptor expressed on myeloid cells1 (TREM-1), inflammation amplifier, is upregulated in ARDS and COVID-19. In animals, TREM-1 blockade reduces cytokine storm and protects against lung injury. The hypothesis of this study supported by recent animal data is that TREM-1 blockade ameliorates ARDS. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize risk of failure in clinical development, we developed a first-in-class ligand-independent well- tolerated TREM-1 inhibitory peptide GF9 that can be formulated into SignaBlok's long half-life macrophage- specific lipopeptide complexes (LPC) to improve its half-life and targeting to the inflammation areas. Earlier, we showed that GF9 sequence either as a free peptide or as a part of LPC-bound trifunctional peptide GA31 (GA31-LPC) suppresses inflammatory cytokine release, protects against septic shock and reverses lung fibrosis in mice. This study aims to test if it suppresses cytokine storm and alleviates ARDS in an animal model. Considering the pros and cons of GF9 and GA31-LPC, we suggest to test both leads. Specific aims of this project are to: 1) generate and characterize in vitro GF9 and GA31-LPC injectables, and 2) test GF9 and GA31-LPC comparatively in an animal model of ARDS. We will synthesize and characterize GF9 and GA31-LPC for their stability, rate and efficiency of macrophage uptake in vitro as well as for their inhibitory effect on cytokine release by LPS-stimulated cells. We will test two doses of the formulations in ARDS animals. Ligand-dependent TREM-1 inhibitor LR12 will be studied comparatively. We will analyze lung inflammation and lung damage. Comprehensive Histo/IHC studies will be performed. It is anticipated that that this Phase I study will identify a novel, first-in-class, well-tolerable agent as a powerful platform for development of safe and effective therapy capable of treating ARDS. Its anticipated safety is supported by good tolerability of SignaBlok's GF9 therapy in animals and by safety of TREM-1- blocking approach in healthy, septic and COVID-19 subjects. If successful, Phase I will be followed in Phase II by toxicology, ADME, pharmacology and CMC studies, filing an IND and evaluation in humans.

Public Health Relevance Statement:
Project Narrative Every year, 150,000 Americans are affected by acute respiratory distress syndrome (ARDS), an inflammatory lung condition that may complicate severe pneumonia (including influenza and COVID-19), trauma, sepsis, cancer, and many other conditions. ARDS is fatal in 30 to 40% of cases. Around 5% of COVID-19 patients develop severe ARDS that is a common cause of death related to COVID-19. Soluble TREM-1 (sTREM-1) level has the best prognostic accuracy for 30-day intubation/mortality in COVID-19 patients and TREM-1 is now a target in COVID-19. The proposed research is anticipated to result in the development of novel mechanism-based ARDS therapy that could substantially reduce the mortality rate in COVID-19 and other patients with ARDS and improve outcomes in these high risk groups.

Project Terms:
Affect; Amplifiers; Animals; inhibitor; Arthritis; arthritic; Beds; Bleomycin; Bleo; Body Weight Changes; Weight Change; Bordetella pertussis; B pertussis; B. pertussis; H Pertussis; H. 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heavy metal lead; Ligands; Liver diseases; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; Lung; Lung Respiratory System; pulmonary; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; disease of the lung; disorder of the lung; lung disorder; Macrophage; M?; mortality; Mus; Mice; Mice Mammals; Murine; Patients; Peptides; Pharmacology; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Pneumonia; Pulmonary Fibrosis; Lung Tissue Fibrosis; fibrosis in the lung; lung fibrosis; Research; Acute Respiratory Distress Syndrome; ARDS; Acute Respiratory Distress; Adult ARDS; Adult RDS; Adult Respiratory Distress Syndrome; Da Nang Lung; Shock Lung; Stiff lung; wet lung; Risk; Safety; Endotoxic Shock; Septic Shock; Survival Rate; Testing; Toxicology; Pertussis; B pertussis infection; B. pertussis infection; Bordetella pertussis infection; Whooping Cough; infected with B pertussis; infected with B. pertussis; infected with Burkholderia pertussis; cytokine; Macrophage Colony-Stimulating Factor; CSF-1; Colony-Stimulating Factor 1; M-CSF; CSIF; CSIF-10; Cytokine Synthesis Inhibitory Factor; IL-10; IL10; IL10A; Interleukin 10 Precursor; Interleukin-10; Injectable; improved; Area; Acute; Phase; Evaluation; prognostic; Blood Serum; Serum; Failure; uptake; Lung damage; pulmonary damage; pulmonary injury; pulmonary tissue damage; pulmonary tissue injury; lung injury; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Therapeutic; Inflammatory; septic; Complex; Clinic; American; receptor; Receptor Protein; animal data; Animal Model; Animal Models and Related Studies; model of animal; novel; TNF gene; (TNF)-?; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-?; TNFA; TNF?; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Myeloid Cells; Inflammatory Response; Molecular Interaction; Binding; CCL2 gene; CCL2; Chemokine, CC Motif, Ligand 2; MCAF; MCP-1; MCP1; Monocyte Chemoattractant Protein-1; Monocyte Chemotactic Protein-1; Monocyte Chemotactic and Activating Factor; Monocyte Chemotactic and Activating Protein; Monocyte Chemotactive and Activating Factor; Monocyte Secretory Protein JE; SCYA2; Small Inducible Cytokine A2; Dose; Data; Cancer Patient; Development; developmental; blood infection; bloodstream infection; Sepsis; Population; Trauma; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; comparative; prototype; overexpress; overexpression; effective treatment; effective therapy; risk minimization; Phase I Study; phase 1 study; Drug Targeting; Lung Inflammation; Pneumonitis; Pulmonary Inflammation; Formulation; improved outcome; high risk group; high risk individual; high risk people; high risk population; clinical development; cytokine storm; 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